Cancer is one of the leading causes of death in the developed world, with over one million people diagnosed with cancer and 500,000 deaths per year in the United States alone. Overall it is estimated that more than 1 in 3 people will develop some form of cancer during their lifetime. There are more than 200 different types of cancer, four of which—breast, lung, colorectal, and prostate—account for almost half of all new cases (Siegel et al., 2011, CA: A Cancer J. Clin. 61:212-236).
Signaling pathways normally connect extracellular signals to the nucleus leading to expression of genes that directly or indirectly control cell growth, differentiation, survival, and death. In a wide variety of cancers, signaling pathways are dysregulated and may be linked to tumor initiation and/or progression. Signaling pathways implicated in human oncogenesis include, but are not limited to, the WNT pathway, the Ras-Raf-MEK-ERK or MAPK pathway, the PI3K-AKT pathway, the MET/HGF pathway, the CDKN2A/CDK4 pathway, the Bcl-2/TP53 pathway, and the NOTCH pathway.
The MET/HGF (hepatocyte growth factor) pathway has been shown to play a critical role in early embryonic development. However, in adult tissues the MET pathway is tightly controlled and primarily quiescent in its growth signaling program, except in processes such as wound repair. Dysregulation of the MET pathway may lead to cell proliferation, protection from apoptosis, angiogenesis, invasion, and metastasis. MET may be dysregulated by a variety of different mechanisms including protein over-expression, constitutive activation, ligand-dependent activation, gene amplification, gene mutation, and/or MET modifications (e.g., phosphorylation). The MET pathway has been shown to be dysregulated in many tumor types, including but not limited to, lung, colorectal, breast, liver, gastric, pancreas, and brain.
The WNT signaling pathway is one of several critical regulators of embryonic pattern formation, post-embryonic tissue maintenance, and stem cell biology. More specifically, WNT signaling plays an important role in the generation of cell polarity and cell fate specification including self-renewal by stem cell populations. Unregulated activation of the WNT pathway is associated with numerous human cancers where it is believed the activation can alter the developmental fate of cells. The activation of the WNT pathway may maintain tumor cells in an undifferentiated state and/or lead to uncontrolled proliferation. Thus, carcinogenesis can proceed by overtaking homeostatic mechanisms that control normal development and tissue repair (reviewed in Reya & Clevers, 2005, Nature, 434:843-50; Beachy et al., 2004, Nature, 432:324-31).
The MET pathway and the WNT pathway have both been identified as potential targets for cancer therapy. It is one of the objectives of the present invention to provide improved molecules for cancer treatment, particularly bispecific agents that specifically bind human MET and one or more WNT proteins. Another objective of the invention is to use these novel bispecific agents to modulate the MET pathway and the WNT pathway and inhibit tumor growth.